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Chronic Myeloproliferative Neoplasias

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

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Abstract

Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development leads to systemic mastocytosis (SM), a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused MC accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil–MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.

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Acknowledgements

We thank Cem Akin, Alberto Orfao, Ann Dvorak, David Weinstock, Susan Buchanan, Girijesh Buruzula, Joyce LaVecchio, Atsuya Wakabayashi, Jacobo Ramirez, Elsa Lindhe, Louise Trakimas and Maria Ericsson of the HMS electron microscopy core facility, and the DF/HCC Specialized Histopathology facility for their assistance. This work was supported by a Damon Runyon-Sohn Foundation Cancer Research Fellowship (DRSG 02-12) and a St. Baldrick’s Foundation-PALS Scholar Award (243625; LDW), a Helen Hay Whitney Cancer Fellowship (SD), a Burroughs-Wellcome Fund Career Award (HZ), and grants from the NIH (R01-HL088582 and P30DK036836; AJW), (R01-GM107536; GQD), (K08-CA157727; HZ) and the Ellison Medical Foundation (GQD).

Author Contributions

LDW, TNR, DSP, RGR, GQD, and AJW designed experiments and interpreted data. LDW, TNR, PTN, DSP, JLS, and RGR performed experiments. SD, HZ, and GQD developed and characterized transgenic mice. RCL and DJD provided samples through DFCI Protocol 01-206. LDW wrote the manuscript; LDW, RGR, TNR, DJD, DSP, GQD, and AJW edited it.

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Author notes

  1. L D Wang, T N Rao and R G Rowe: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Joslin Diabetes Center, Boston, MA, USA

    L D Wang, T N Rao, P T Nguyen, J L Sullivan & A J Wagers

  2. Harvard Stem Cell Institute, Cambridge, MA, USA

    L D Wang, T N Rao, R G Rowe, P T Nguyen, J L Sullivan, D S Pearson, S Doulatov, G Q Daley & A J Wagers

  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    L D Wang, T N Rao, P T Nguyen, J L Sullivan, G Q Daley & A J Wagers

  4. Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Dana-Farber/Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA

    L D Wang, R G Rowe, D S Pearson, S Doulatov & G Q Daley

  5. Department of Medicine, Boston Children’s Hospital, Boston, MA, USA

    L D Wang, R G Rowe, D S Pearson, S Doulatov & G Q Daley

  6. Manton Center for Orphan Disease Research, Boston, MA, USA

    R G Rowe, D S Pearson, S Doulatov & G Q Daley

  7. Howard Hughes Medical Institute, Boston, MA, USA

    R G Rowe, D S Pearson, S Doulatov, G Q Daley & A J Wagers

  8. Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA

    D S Pearson & G Q Daley

  9. Department of Pediatrics and Internal Medicine, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    L Wu & H Zhu

  10. Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    L Wu

  11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    R C Lindsley & D J DeAngelo

  12. Division of Hematology, Brigham and Women’s Hospital, Boston, MA, USA

    R C Lindsley

  13. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    G Q Daley

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  1. L D Wang
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  2. T N Rao
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  3. R G Rowe
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  4. P T Nguyen
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  5. J L Sullivan
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  6. D S Pearson
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  7. S Doulatov
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  8. L Wu
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  9. R C Lindsley
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  10. H Zhu
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  11. D J DeAngelo
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  12. G Q Daley
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Correspondence to A J Wagers.

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Wang, L., Rao, T., Rowe, R. et al. The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy. Leukemia 29, 1320–1330 (2015). https://doi.org/10.1038/leu.2015.19

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